Association of osteoporosis with sarcopenia and its components among community-dwelling older Chinese adults with different obesity levels: A cross-sectional study.

We aimed to investigate whether sarcopenia and its components are associated with osteoporosis in community-dwelling older Chinese adults with different obesity levels. This cross-sectional study included 1938 participants (42.1% male) with a mean age of 72.1 ±â€…5.9 years. The categorization of individuals into various weight categories was based on the Working Group on Obesity in China's criteria, utilizing the body mass index (BMI) as follows: underweight, BMI < 18.5 kg/m2; normal weight, 18.5 ≤ BMI < 24 kg/m2; overweight, 24 ≤ BMI < 28 kg/m2; and obesity, BMI ≥ 28 kg/m2. In this research, the osteoporosis definition put forth by the World Health Organization (bone mineral density T-score less than or equal to -2.5 as assessed by Dual-energy X-ray absorptiometry (DXA)). Sarcopenia was defined according to the diagnostic criteria of the Asian Working Group for Sarcopenia. The prevalence of osteoporosis was highest in the underweight group and gradually decreased with increasing BMI (Underweight: 55.81% vs Normal weight: 45.33% vs Overweight: 33.69% vs Obesity: 22.39). Sarcopenia was associated with elevated odds of osteoporosis in normal-weight subjects independent of potential covariates (OR = 1.70, 95% CI = 1.22-2.35, P = .002). In normal-weight participants, a higher appendicular skeletal muscle mass index (ASMI) was associated with a reduced risk of osteoporosis (OR = 0.56, 95% CI = 0.42-0.74, P < .001). In this study, we found that the prevalence of osteoporosis was highest in the underweight group and gradually decreased with increasing BMI. Sarcopenia, body fat percentage, and ASMI were associated with elevated odds of osteoporosis in normal-weight subjects independent of potential covariates, and higher percent body fat (PBF) was associated with an increased risk of osteoporosis in overweight people, and no such association was found in other weight groups. Different amounts of adipose tissue and muscle mass may alter bone biology. Further longitudinal follow-up studies are required to more accurately assess the risk of osteoporosis and sarcopenia in different weight populations. This cross-sectional study found that the prevalence of osteoporosis was highest in the underweight group and gradually decreased with increasing BMI. Sarcopenia was associated with elevated odds of osteoporosis in normal-weight subjects independent of potential covariates.

Toll-like receptor 9 signaling is associated with immune responses to Trypanosoma brucei infection.

Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system. Toll-like receptor 9 (TLR9) is a key modulator for resistance to host-infective trypanosomes; however, the underlying molecular mechanism remains indistinct. Thus, we first approached the issue using Tlr9-mutant mice that render them non-responsive to TLR9 agonists. After infection, T cells in the spleens of Tlr9-mutant mice were analyzed by flow cytometry and a reduction in CD8+, CD4+ T, and NKT cells was observed in Tlr9-mutant mice compared to WT mice. We further found that the responses of inflammatory cytokines in the sera were reduced in Tlr9-mutant mice after T. brucei infection. The underlying molecular mechanism was that T. b. brucei DNA activated TLR9, which consequently upregulated the expression of p38 and ERK/MAPK, resulting in host resistance to trypanosome infection. In conclusion, these findings provide novel insights into the TLR9-mediated host responses to trypanosome infection.

Deep Learning Combined with Radiologist's Intervention Achieves Accurate Segmentation of Hepatocellular Carcinoma in Dual-Phase Magnetic Resonance Images.

Purpose: Segmentation of hepatocellular carcinoma (HCC) is crucial; however, manual segmentation is subjective and time-consuming. Accurate and automatic lesion contouring for HCC is desirable in clinical practice. In response to this need, our study introduced a segmentation approach for HCC combining deep convolutional neural networks (DCNNs) and radiologist intervention in magnetic resonance imaging (MRI). We sought to design a segmentation method with a deep learning method that automatically segments using manual location information for moderately experienced radiologists. In addition, we verified the viability of this method to assist radiologists in accurate and fast lesion segmentation. Method: In our study, we developed a semiautomatic approach for segmenting HCC using DCNN in conjunction with radiologist intervention in dual-phase gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid- (Gd-EOB-DTPA-) enhanced MRI. We developed a DCNN and deep fusion network (DFN) trained on full-size images, namely, DCNN-F and DFN-F. Furthermore, DFN was applied to the image blocks containing tumor lesions that were roughly contoured by a radiologist with 10 years of experience in abdominal MRI, and this method was named DFN-R. Another radiologist with five years of experience (moderate experience) performed tumor lesion contouring for comparison with our proposed methods. The ground truth image was contoured by an experienced radiologist and reviewed by an independent experienced radiologist. Results: The mean DSC of DCNN-F, DFN-F, and DFN-R was 0.69 ± 0.20 (median, 0.72), 0.74 ± 0.21 (median, 0.77), and 0.83 ± 0.13 (median, 0.88), respectively. The mean DSC of the segmentation by the radiologist with moderate experience was 0.79 ± 0.11 (median, 0.83), which was lower than the performance of DFN-R. Conclusions: Deep learning using dual-phase MRI shows great potential for HCC lesion segmentation. The radiologist-aided semiautomated method (DFN-R) achieved improved performance compared to manual contouring by the radiologist with moderate experience, although the difference was not statistically significant.

CT-based radiomics signature of visceral adipose tissue for prediction of disease progression in patients with Crohn's disease: A multicentre cohort study.

Background: Visceral adipose tissue (VAT) is involved in the pathogenesis of Crohn's disease (CD). However, data describing its effects on CD progression remain scarce. We developed and validated a VAT-radiomics model (RM) using computed tomography (CT) images to predict disease progression in patients with CD and compared it with a subcutaneous adipose tissue (SAT)-RM. Methods: This retrospective study included 256 patients with CD (training, n = 156; test, n = 100) who underwent baseline CT examinations from June 19, 2015 to June 14, 2020 at three tertiary referral centres (The First Affiliated Hospital of Sun Yat-Sen University, The First Affiliated Hospital of Shantou University Medical College, and The First People's Hospital of Foshan City) in China. Disease progression referred to the development of penetrating or stricturing diseases or the requirement for CD-related surgeries during follow-up. A total of 1130 radiomics features were extracted from VAT on CT in the training cohort, and a machine-learning-based VAT-RM was developed to predict disease progression using selected reproducible features and validated in an external test cohort. Using the same modeling methodology, a SAT-RM was developed and compared with the VAT-RM. Findings: The VAT-RM exhibited satisfactory performance for predicting disease progression in total test cohort (the area under the ROC curve [AUC] = 0.850, 95% confidence Interval [CI] 0.764-0.913, P < 0.001) and in test cohorts 1 (AUC = 0.820, 95% CI 0.687-0.914, P < 0.001) and 2 (AUC = 0.871, 95% CI 0.744-0.949, P < 0.001). No significant differences in AUC were observed between test cohorts 1 and 2 (P = 0.673), suggesting considerable efficacy and robustness of the VAT-RM. In the total test cohort, the AUC of the VAT-RM for predicting disease progression was higher than that of SAT-RM (AUC = 0.786, 95% CI 0.692-0.861, P < 0.001). On multivariate Cox regression analysis, the VAT-RM (hazard ratio [HR] = 9.285, P = 0.005) was the most important independent predictor, followed by the SAT-RM (HR = 3.280, P = 0.060). Decision curve analysis further confirmed the better net benefit of the VAT-RM than the SAT-RM. Moreover, the SAT-RM failed to significantly improve predictive efficacy after it was added to the VAT-RM (integrated discrimination improvement = 0.031, P = 0.102). Interpretation: Our results suggest that VAT is an important determinant of disease progression in patients with CD. Our VAT-RM allows the accurate identification of high-risk patients prone to disease progression and offers notable advantages over SAT-RM. Funding: This study was supported by the National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Nature Science Foundation of Shenzhen, and Young S&T Talent Training Program of Guangdong Provincial Association for S&T. Translation: For the Chinese translation of the abstract see Supplementary Materials section.

Fluoxetine shows neuroprotective effects against LPS-induced neuroinflammation via the Notch signaling pathway.

AIM: To determine the neuroprotective effects of fluoxetine on depression-like and motor behaviors in rats treated with lipopolysaccharide (LPS) and the mechanisms involved. METHODS: A rat model of depression in Parkinson's disease (dPD) was established by administering LPS (0.5 mg/kg, i.p.) for 4 days. The sucrose preference test (SPT), open field test (OFT), and rotarod test evaluated depression-like and motor behaviors. White matter fiber integrity and intrinsic activity in the brain were assessed using magnetic resonance imaging. For pathological and molecular expression detection, hematoxylin-eosin staining, immunohistochemistry, Luminex technology, western blotting, and quantitative real-time PCR were used. RESULTS: Fluoxetine increased the sucrose preference in the SPT, the horizontal and center distances in the OFT, and the standing time in the rotarod test. Fluoxetine also improved intrinsic activities and white matter fiber damage in the brain, increased c-Fos expression, reduced Iba-1 expression in the prefrontal cortex, hippocampus, and substantia nigra, and increased TH expression in the substantia nigra. Fluoxetine reduced the concentration of inflammatory cytokines (IL-1α, IL-6, TNF-α, and IFN-γ). The gene and protein expression of Notch1, Jagged1, Hes1, and Hes5 were significantly lower than the LPS group after treatment with fluoxetine. CONCLUSION: Fluoxetine plays neuroprotective effects in relieving LPS-induced depression-like and motor behaviors. The underlying mechanisms may be related to inhibiting microglial activation, regulating the Notch signaling pathway, and inhibiting the inflammatory response.

Graphene quantum dots induce cascadic apoptosis via interaction with proteins associated with anti-oxidation after endocytosis by Trypanosoma brucei.

Trypanosoma brucei, the pathogen causing African sleeping sickness (trypanosomiasis) in humans, causes debilitating diseases in many regions of the world, but mainly in African countries with tropical and subtropical climates. Enormous efforts have been devoted to controlling trypanosomiasis, including expanding vector control programs, searching for novel anti-trypanosomial agents, and developing vaccines, but with limited success. In this study, we systematically investigated the effect of graphene quantum dots (GQDs) on trypanosomal parasites and their underlying mechanisms. Ultrasmall-sized GQDs can be efficiently endocytosed by T. brucei and with no toxicity to mammalian-derived cells, triggering a cascade of apoptotic reactions, including mitochondrial disorder, intracellular reactive oxygen species (ROS) elevation, Ca2+ accumulation, DNA fragmentation, adenosine triphosphate (ATP) synthesis impairment, and cell cycle arrest. All of these were caused by the direct interaction between GQDs and the proteins associated with cell apoptosis and anti-oxidation responses, such as trypanothione reductase (TryR), a key protein in anti-oxidation. GQDs specifically inhibited the enzymatic activity of TryR, leading to a reduction in the antioxidant capacity and, ultimately, parasite apoptotic death. These data, for the first time, provide a basis for the exploration of GQDs in the development of anti-trypanosomials.

LPS activates neuroinflammatory pathways to induce depression in Parkinson's disease-like condition.

Aim: This study aimed to observe the effects of lipopolysaccharide (LPS) intraperitoneal (i.p.) injection on rats and investigate how neuroinflammation contributes to the pathogenesis of depression in Parkinson's disease (dPD). Methods: Rats were administered LPS (0.5 mg/kg, i.p.) for either 1, 2, or 4 consecutive days to establish a rat model of dPD. The sucrose preference test (SPT), the open field test (OFT), and the rotarod test evaluated depression-like and motor behaviors. Magnetic resonance imaging was used to detect alterations in the intrinsic activity and the integrity of white matter fibers in the brain. The expression of c-Fos, ionized calcium-binding adapter molecule (Iba-1), and tyrosine hydroxylase (TH) was evaluated using immunohistochemistry. The concentration of interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and interleukin-10 (IL-10) was measured using Luminex technology. Results: LPS i.p. injections decreased sucrose preference in the SPT, horizontal and center distance in the OFT, and standing time in the rotarod test. The intrinsic activities in the hippocampus (HIP) were significantly reduced in the LPS-4 d group. The integrity of white matter fibers was greatly destroyed within 4 days of LPS treatment. The expression of c-Fos and Iba-1 in the prefrontal cortex, HIP, and substantia nigra increased dramatically, and the number of TH+ neurons in the substantia nigra decreased considerably after LPS injection. The levels of IL-6, TNF-α, and IL-10 were higher in the LPS-4 d group than those in the control group. Conclusion: Injection of LPS (0.5 mg/kg, i.p.) for 4 consecutive days can activate microglia, cause the release of inflammatory cytokines, reduce intrinsic activities in the HIP, destroy the integrity of white matter fibers, induce anhedonia and behavioral despair, and finally lead to dPD. This study proved that LPS injection (0.5 mg/kg, i.p.) for 4 consecutive days could be used to successfully create a rat model of dPD.

Construction of a Prognostic Model for Hypoxia-Related LncRNAs and Prediction of the Immune Landscape in the Digestive System Pan-Cancer.

Digestive system pan-cancer is a general term for digestive system tumors including colorectal carcinoma (CRC), esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), and liver hepatocellular carcinoma (LIHC). Since the anatomical location, function and metabolism are closely related, there may be similarities in development and progression of these tumors. Hypoxia is the consequence of an imbalance between oxygen demand and supply, and intracellular hypoxia is associated with malignant progression, treatment resistance, and poor prognosis in tumors. Therefore, an urgent and challenging task is to investigate the molecular mechanisms associated with hypoxia in digestive system pan-cancer for the prognosis and treatment of digestive tract tumors. In this study, we identified 18 hypoxia-related lncRNAs (HRlncRNAs) by co-expression analysis between hypoxia genes and lncRNAs from digestive system pan-cancer. Six HRlncRNAs were then obtained using lasso regression and multivariate cox analysis to construct a prognostic model. Next, the Akaike information criterion (AIC) values for 3-year receiver operating curve (ROC) were counted to determine the cut-off point and establish an optimal model to distinguish between high- or low-risk groups among patients with digestive system pan-cancer. To evaluate the stability of the prognosis model, we validated it in terms of survival outcomes, clinicopathological stage, tumor-infiltrating immune cells, immune checkpoint inhibitors (ICIs) and anticancer drugs sensitivity. The results suggested that high- risk group had a worse prognosis and a more positive association with tumor-infiltrating immune cells such as B cells, cancer-associated fibroblasts, endothelial cells, monocytes, macrophages and bone marrow dendritic cells in digestive system pan-cancer. Immune checkpoint inhibitors (ICIs) related biomarkers discovered that high-risk group was positively correlated with high expression of HAVCR2 in digestive system pan-cancer. The anticancer drugs sensitivity analysis showed that the high-risk group was associated with the lower half-inhibitory centration (IC50) of Imatinib in digestive system pan-cancer. In conclusion, the prognostic model of HRlncRNAs showed a promising clinical prediction value and may provide a useful reference for the diagnosis and treatment of the digestive system tumors.

CBX7 represses the POU2F2 to inhibit the PD-L1 expression and regulate the immune response in bladder cancer.

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system worldwide. To date, immune checkpoint inhibitors (including PD-1/PD-L1) have been applied to treat patients with bladder cancer in the clinic and achieved the promising outcome. Further improvement of the anticancer efficiency of these immune therapies is crucial for bladder cancer. Our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress PD-L1 expression and PD-1 checkpoint pathway in cancer. In this study, we revealed that CBX7 downregulated the expression of POU2F2 that indirectly repressed the PD-L1 in BC cells. Depletion of CBX7 resulted in resistance to PD-1 blockade in bladder cancer. Collectively, our results suggested that the CBX7/POU2F2/PD-L1 axis plays an important role in determining the antitumor effect of PD-1 blockade in bladder cancer.

Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei.

Lysine lactylation has been recognized as a novel post-translational modification occurring on histones. However, lactylation in non-histone proteins, especially in proteins of early branching organisms, is not well understood. Energy metabolism and the histone repertoire in the early diverging protozoan parasite Trypanosoma brucei, the causative agent of African trypanosomiasis, markedly diverge from those of conventional eukaryotes. Here, we present the first exhaustive proteome-wide investigation of lactylated sites in T. brucei. We identified 387 lysine-lactylated sites in 257 proteins of various cellular localizations and biological functions. Further, we revealed that glucose metabolism critically regulates protein lactylation in T. brucei although the parasite lacks lactate dehydrogenase. However, unlike mammals, increasing the glucose concentration reduced the level of lactate, and protein lactylation decreased in T. brucei via a unique lactate production pathway. In addition to providing a valuable resource, these foregoing data reveal the regulatory roles of protein lactylation of trypanosomes in energy metabolism and gene expression.

Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation.

Type 2 diabetes mellitus (T2DM), a chronic low-grade inflammatory disease with high morbidity and mortality, is a serious threat to public health. Previously we demonstrated that a traditional Chinese medicine formulation, Jiedu Tongluo Tiaogan Formula (JDTL), exerted a favorable hypoglycemic effect due to unknown molecular mechanisms involving interactions among JDTL compounds and various cellular components. This study aimed to explore JDTL mechanisms for alleviating hyperglycemia using an integrated strategy incorporating system pharmacology, bioinformatics analysis, and experimental verification. This strategy entailed initial elucidation of JDTL chemical composition using fingerprint analysis via high performance liquid chromatography (HPLC). Next, functions of putative shared target genes and associated pathways were deduced using GO and KEGG pathway enrichment and molecular docking analyses. Ultimately, targets associated with JTDL anti-T2DM effects were found to be functionally associated with biological functions related to lipopolysaccharide and cytokine receptor binding. These results implicated PI3K-Akt signaling pathway involvement in JDTL anti-T2DM effects, as this pathway had been previously shown to play significant roles in glucose and lipid metabolism-related diseases. Furthermore, addition of JDTL to INS-1 and HepG2 cell cultures stimulated cellular mRNA-level and protein-level expression leading to enhanced production of IRS1, Akt, and PI3K. In summary, here JDTL bioactive ingredients, potential targets, and molecular mechanisms underlying JDTL anti-T2DM effects were identified using a multi-component, multi-target, and multi-channel analytical approach, thus providing an important scientific foundation to facilitate development of new drugs mechanistic strategies for preventing and treating T2DM.

Expression and prognosis of CDC45 in cervical cancer based on the GEO database.

Cervical cancer is one of the most common malignant tumors in women, and its morbidity and mortality are increasing year by year worldwide. Therefore, an urgent and challenging task is to identify potential biomarkers for cervical cancer. This study aims to identify the hub genes based on the GEO database and then validate their prognostic values in cervical cancer by multiple databases. By analysis, we obtained 83 co-expressed differential genes from the GEO database (GSE63514, GSE67522 and GSE39001). GO and KEGG enrichment analysis showed that these 83 co-expressed it mainly involved differential genes in DNA replication, cell division, cell cycle, etc.. The PPI network was constructed and top 10 genes with protein-protein interaction were selected. Then, we validated ten genes using some databases such as TCGA, GTEx and oncomine. Survival analysis demonstrated significant differences in CDC45, RFC4, TOP2A. Differential expression analysis showed that these genes were highly expressed in cervical cancer tissues. Furthermore, univariate and multivariate cox regression analysis indicated that CDC45 and clinical stage IV were independent prognostic factors for cervical cancer. In addition, the HPA database validated the protein expression level of CDC45 in cervical cancer. Further studies investigated the relationship between CDC45 and tumor-infiltrating immune cells via CIBERSORT. Finally, gene set enrichment analysis (GSEA) showed CDC45 related genes were mainly enriched in cell cycle, chromosome, catalytic activity acting on DNA, etc. These results suggested CDC45 may be a potential biomarker associated with the prognosis of cervical cancer.

LNCAROD enhances hepatocellular carcinoma malignancy by activating glycolysis through induction of pyruvate kinase isoform PKM2.

BACKGROUND: Mounting evidence has suggested the essential role of long non-coding RNAs (lncRNAs) in a plethora of malignant tumors, including hepatocellular carcinoma. However, the underlyling mechanisms of lncRNAs remain unidentified in HCC. The present work was aimed to explore the regulatory functions and mechanisms of LncRNA LNCAROD in HCC progression and chemotherapeutic response. METHODS: The expression of LNCAROD in HCC tissues and cell lines were detected by quantitative reverse transcription PCR (qPCR). Cancer cell proliferation, migration, invasion, and chemoresistance were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and chemosensitivity assays. Methylated RNA immunoprecipitation qRCR (MeRIP-qPCR) was used to determine N6-methyladenosine (m6A) modification level. RNA immunoprecipitation (RIP) and RNA pull down were applied to identify the molecular sponge role of LNCAROD for modulation of miR-145-5p via the competing endogenous RNA (ceRNA) mechanism, as well as the interaction between LNCAROD and serine-and arginine-rich splicing factor 3 (SRSF3). The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and LNCAROD was also identified by RIP assay. Gain- or-loss-of-function assays were used to identify the function and underlying mechanisms of LNCAROD in HCC. RESULTS: We found that LNCAROD was significantly upregulated and predicted a poorer prognosis in HCC patients. LNCAROD upregulation was maintained by increased m6A methylation-mediated RNA stability. LNCAROD significantly promoted HCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo. Furthermore, mechanistic studies revealed that pyruvate kinase isoform M2 (PKM2)-mediated glycolysis enhancement is critical for the role of LNACROD in HCC. According to bioinformatics prediction and our experimental data, LNCAROD directly binds to SRSF3 to induce PKM switching towards PKM2 and maintains PKM2 levels in HCC by acting as a ceRNA against miR-145-5p. The oncogenic effects of LNCAROD in HCC were more prominent under hypoxia than normoxia due to the upregulation of hypoxia-triggered hypoxia-inducible factor 1α. CONCLUSIONS: In summary, our present study suggests that LNCAROD induces PKM2 upregulation via simultaneously enhancing SRSF3-mediated PKM switching to PKM2 and sponging miR-145-5p to increase PKM2 level, eventually increasing cancer cell aerobic glycolysis to participate in tumor malignancy and chemoresistance, especially under hypoxic microenvironment. This study provides a promising diagnostic marker and therapeutic target for HCC patients.

Effect of biochar-immobilized Sphingomonas sp. PJ2 on bioremediation of PAHs and bacterial community composition in saline soil.

This study aimed to investigate the bioremediation efficiency and bacterial regulation mechanism of biochar-immobilized bacterium (BM) in polycyclic aromatic hydrocarbon (PAH)-contaminated saline soil by conducting pot experiments. In BM treatment, PAH-degrading strain Sphingomonas sp. PJ2 was inoculated into biochar produced at 400 °C and 600 °C using the pine needles (BM400 and BM600). The removal rates of PAHs, soil physicochemical properties, abundance of PAH-ring hydroxylating dioxygenase (PAH-RHD), and bacterial community composition were determined. After 60 days of bioremediation, BM treatment significantly (P < 0.05) increased the removal rate of PAHs compared with biochar and PJ2 alone (15.94% and 37.3%, respectively). BM treatment clearly improved the physicochemical properties of saline soil. Moreover, the amount of Gram-positive PAH degraders increased in BM-treated soils compared with other treatments, and their gene abundance had a strong positive correlation with the removal rates of PAHs in soils (r = 0.896; P < 0.01). Furthermore, BM treatment increased the abundance of Sphingomonas genus, indicating that the strain PJ2 could survive and colonize in PAH-contaminated saline soil under the protection of biochar. This study provided an effective and green approach for the remediation and improvement of the PAH-contaminated saline soil.

TatD DNases of African trypanosomes confer resistance to host neutrophil extracellular traps.

African trypanosomatid parasites escape host acquired immune responses through periodic antigenic variation of their surface coat. In this study, we describe a mechanism by which the parasites counteract innate immune responses. Two TatD DNases were identified in each of Trypanosoma evansi and Trypanosoma brucei. These DNases are bivalent metal-dependent endonucleases localized in the cytoplasm and flagella of the parasites that can also be secreted by the parasites. These enzymes possess conserved functional domains and have efficient DNA hydrolysis activity. Host neutrophil extracellular traps (NETs) induced by the parasites could be hydrolyzed by native and recombinant TatD DNases. NET disruption was prevented, and the survival rate of parasites was decreased, in the presence of the DNase inhibitor aurintricarboxylic acid. These data suggest that trypanosomes can counteract host innate immune responses by active secretion of TatD DNases to degrade NETs.

A Study on the Mechanism of Milkvetch Root in the Treatment of Diabetic Nephropathy Based on Network Pharmacology.

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. Owing to its complicated pathogenesis, no satisfactory treatment strategies for DN are available. Milkvetch Root is a common traditional Chinese medicine (TCM) and has been extensively used to treat DN in clinical practice in China for many years. However, due to the complexity of botanical ingredients, the exact pharmacological mechanism of Milkvetch Root in treating DN has not been completely elucidated. The aim of this study was to explore the active components and potential mechanism of Milkvetch Root by using a systems pharmacology approach. First, the components and targets of Milkvetch Root were analyzed by using the Traditional Chinese Medicine Systems Pharmacology database. We found the common targets of Milkvetch Root and DN constructed a protein-protein interaction (PPI) network using STRING and screened the key targets via topological analysis. Enrichment of Gene Ontology (GO) pathways and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed. Subsequently, major hubs were identified and imported to the Database for Annotation, Visualization and Integrated Discovery for pathway enrichment analysis. The binding activity and targets of the active components of Milkvetch Root were verified by using the molecular docking software SYBYL. Finally, we found 20 active components in Milkvetch Root. Moreover, the enrichment analysis of GO and KEGG pathways suggested that AGE-RAGE signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway, and TNF signaling pathway might be the key pathways for the treatment of DN; more importantly, 10 putative targets of Milkvetch Root (AKT1, VEGFA, IL-6, PPARG, CCL2, NOS3, SERPINE1, CRP, ICAM1, and SLC2A) were identified to be of great significance in regulating these biological processes and pathways. This study provides an important scientific basis for further elucidating the mechanism of Milkvetch Root in treating DN.

Landscapes of Protein Posttranslational Modifications of African Trypanosoma Parasites.

Proteins of all living cells undergo a myriad of post-translational modifications (PTMs) that are critical to multifarious life processes. In this study, we describe the first comprehensive multiple PTM-omics atlas in parallel with quantitative proteome analyses of two representative species of African trypanosomes, Trypanosoma brucei and Trypanosoma evansi. Ten PTM types with approximately 40,000 modified sites and 150 histone marks with a fine map on each protein of the two African trypanosomes were accomplished. The two biologically different trypanosomal species displayed distinct PTM-omic features, regulation pathways, and networks. Modifications in the proteins involved in the redox system were mainly upregulated in T. brucei, whereas proteins associated with motility were predominantly modified in T. evansi. The establishment of a database of multiple PTMs in the two parasites provides us with a deep insight into the biological mechanisms that underpin life processes in trypanosomes with different life cycles.

Network Pharmacology-based Investigation of the Underlying Mechanism of Panax notoginseng Treatment of Diabetic Retinopathy.

BACKGROUND: Panax notoginseng, a Chinese herbal medicine, has been widely used to treat vascular diseases. Diabetic retinopathy (DR) is one of the complications of diabetic microangiopathy. According to recent studies, the application of Panax notoginseng extract and related Chinese patent medicine preparations can significantly improve DR. However, the pharmacological mechanisms remain unclear. Therefore, the purpose of this study was to decipher the potential mechanism of Panax notoginseng treatment of DR using network pharmacology. METHODS: We evaluated and screened the active compounds of Panax notoginseng using the Traditional Chinese Medicine Systems Pharmacology database and collected potential targets of the compounds by target fishing. A multi-source database was also used to organize targets of DR. The potential targets as the treatment of DR with Panax notoginseng were then obtained by matching the compound targets with the DR targets. Using protein-protein interaction networks and topological analysis, interactions between potential targets were identified. In addition, we also performed gene ontology-biological process and pathway enrichment analysis for the potential targets by using the Biological Information Annotation Database. RESULTS: Eight active ingredients of Panax notoginseng and 31 potential targets for the treatment of DR were identified. The screening and enrichment analysis revealed that the treatment of DR using Panax notoginseng primarily involved 28 biological processes and 10 related pathways. Further analyses indicated that angiogenesis, inflammatory reactions, and apoptosis may be the main processes involved in the treatment of DR with Panax notoginseng. In addition, we determined that the mechanism of intervention of Panax notoginseng in treating DR may involve five core targets, VEGFA, MMP-9, MMP-2, FGF2, and COX-2. CONCLUSION: Panax notoginseng may treat diabetic retinopathy through the mechanism of network pharmacological analysis. The underlying molecular mechanisms were closely related to the intervention of angiogenesis, inflammation, and apoptosis with VEGFA, MMP-9, MMP-2, FGF2, and COX-2 being possible targets.

Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-ß1 in bladder cancer cells.

BACKGROUND: The effect of competing endogenous RNA (ceRNA) can regulate gene expression by competitively binding microRNAs. Fascin-1 (FSCN1) plays an important role in the regulation of cellular migration and invasion during tumor progression, but how its regulatory mechanism works through the ceRNA effect is still unclear in bladder cancer (BLCA). METHODS: The role of fascin-1, miR-200b, and ZEB1-AS1 in BLCA was investigated in vitro and in vivo. The interaction between fascin-1, miR-200b, and ZEB1-AS1 was identified using bioinformatics analysis, luciferase activity assays, RNA-binding protein immunoprecipitation (RIP), quantitative PCR, and western blotting. Loss (or gain)-of-function experiments were performed to investigate the biological roles of miR-200b and ZEB1-AS1 on migration, invasion, proliferation, cell apoptosis, and cell cycle. RESULTS: ZEB1-AS1 functions as a competing endogenous RNA in BLCA to regulate the expression of fascin-1 through miR-200b. Moreover, the oncogenic long non-coding RNA ZEB1-AS1 was highly expressed in BLCA and positively correlated with high tumor grade, high TNM stage, and reduced survival of patients with BLCA. Moreover, ZEB1-AS1 downregulated the expression of miR-200b, promoted migration, invasion, and proliferation, and inhibited apoptosis in BLCA. Furthermore, we found TGF-ß1 induced migration and invasion in BLCA by regulating the ZEB1-AS1/miR-200b/FSCN1 axis. CONCLUSION: The observations in this study identify an important regulatory mechanism of fascin-1 in BLCA, and the TGF-ß1/ZEB1-AS1/miR-200b/FSCN1 axis may serve as a potential target for cancer therapeutic purposes.